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Stereoselective syntheses of 3,3-difluoro-1-propene derivatives
0040~4039/93$6.00+ .OO
Tetrahedron Letten, Vol. 34, No. 47. pp. 75657566,1993 Printed in Great Britain
Pcrgamon Press Ltd
Stereoselective Syntheses of 3,3-difluoro-1-propene Derivatives F&d&ique TelBerl* and Raymond Sauv&& I-IMU,
hbomtoirc
da Mbdiateuta Cbimiqw,
Domaine de Btwcwy,
7 llm J. el P. weis% 78114 Mqny-laa-H~lu 2-L~bomtoim do Chimie dea Orgdbmda,
(haca)
moci6 8u CNRS, Univcmitc P. c( hi. Curie,
botta 183.4 phce Jussieu,75252 Puis Cdcx 05 (&ace)
Abstntcf: A highIy regia- and stam~eluviw intmdnaion 40 lhe kq step is the treatment qf 3-acet~I.ld&luorA-ptvpe~ and lithium salts.
d@~~mmethylene gtvup in a&k pasition is dacribad with Grigtumi reagents in the presence of wpper
During the past few years, fluorinated organic molecules have drawn much attention due to their unique biological properties. The replacement of hydrogen atoms by fluorine atoms in biological molecules causes only a small steric perturbation but leads to major changes in hydrophobicity and polarity of the hydrocarbon chaint. Some syntheses allowing to prepare products in which a methylene group a to the double bond is replaced by a CF2 group have been describ&5. Herein, we report an efficient method for the incorporation of a difluoromethylene group in an allylic position. We show its application to the synthesis of various alkenes and styrenes. R’R’CzO
Table.
1) CFp=CHLI ____t 2) CH,COCl
R’R’C(OAc)-CHzCF,
Rt
R2
R3
X
Yielda
wzb
n-Hex n-Hex n-Hex n-Hex lhienyl
H H H H H
Me n-Bu i-Er t-Bu t-Bu i-Er
Br Br Br Cl Cl Br
(%) 75c 95 94d 95 70 85
9713 9812 97i3 9515 10010 __
(Cw 5
R’MgX CUCN ) LICI
R’R’CsCH-CF?-R’
19FNMR-&ppm)ICFCl,
Experimental conditions 24hl2O”C 8h/-15°C 2h/-20°C 3h/-20°C lh/-20°C 1h/-30°C
a: yield for the second step; b: E/Z ratio determined by teF NMR; c: containing also 15% of HexCH(Me)CH=C!FMe (Z/E=4/1); d: 80% with only 2 eq. of RsMgX. Our procedure is based on two key steps; an initial reaction between difluorovinyl lithium, prepared with 1, ldifluoroethylene and s-BuLi, and various carbonyl compounds leads to the allylic B,B-difluorinated 7565
7566
alcoxidese, which are acetylated in situ. Secondly, the intermediate acetates are attacked by Grignard reagents in the presence of copper and lithium salts via an S$‘, substitution reaction of an acetate moiety by an alkyl group, to afford the corresponding allylic difluorinated compounds with high regio- and stereoselectivities (no product of SN2 is present and if Rz=H, the E isomer is major (2 95 96)). Experimental procedure: the treatment of carbonyl derivatives with 2,2_difluorovinyl lithium, prepared in sifu from l,l-difluoroethylene
and s-BuLi in THF and Es0
@O/20) at -100°C (15 min), leads to the
difluorinated alcoxides which are acetylated in siru with AcCl (addition at -50°C then 30 min at O’C). In the case where Rt,R2=(CH2)5,
the alcohol is isolated and acetylated (Ac20, 4-DMAP, CH&$,
+2O”C,
2h)‘. To these intermediate acetates (5. 1O-3mol,l eq.), in the presence of CuCN (3 eq.) and LiCl (3 eq.) in THF (40 ml), is added the Grignard reagent (3eq.) (see Table) to afford the allylic difluorinated products which are then purified by flash silica-gel chromatography (pentane). This methodology is exemplified by the preparation of the difluoromethylene allylic analogue of Q-5decenyl acetate, a sex pheromonal component of Grupholifumolesra(oriental fruit moth). Previously, Fried ef al. have reported a synthesis of the same difluorinated analog&t. tEUO(CH~)~MgCI
Ac20 =
pr*
CuCN,LICl
CF,(CH@tBu
-
Pr\//\ FeCl,
CF2(CH&OAc
OAc
The protected Grignard reagent reacts with the adequate acetate to afford the corresponding difluoride ether in 65% yield (steric purity=97%)s.
allylic
The ether function is then deprotected into the acetate
with A%0 and FeCl, in E%O (80% yield, steric purity=93%)s. In conclusion,
this route appears to be a general and highly regioselective method for the allylic
introduction of a difluoromethylene
group into various alkenes and styrenes. This reaction allows us to
prepare readily products of high stereoisomeric and chemical purities, in good overall yields and in two steps from available starting materials. Acknowledgements: lhe authors thank PI@. J.F. Normaru and C. L&coins for helpfur discussions. lhis work was supported by lNRA and Ch!RS. We are indebted to Elf-&o&em for a generous gl@ of ISdifluoroethylene. References and notes 1. Prestwich, G.D. Pestic. Sci. 1986, 37, 430-440.
Prestwich, G.D. ‘; Sun, W.C. ; Mayer, MS. ; Dickens, J.C. J. Chem. Ecol. 1990, Id, 1761-1789. 2. Hasek, W.R. ; Smith, W.C. ; Engelhart, V.A. J. Am. Chem. Sot. l!MO,82,543-551. 3. Kwok, P.Y. ; Muellner, F.W. ; Chen, C.K. ; Fried, J. J. Am. Chem. Sot. 1987,109, 3684-3692; 4. Masnyk, M. ; Fried, J. ; Roelofs, W. TetrahedronLerr. 1989, 30, 3243-3246; 5. Sun, W.C. ; Ng, C.S. ; Prestwich, G.D. J. Org. Chem. 1992,57, 132-137. 6. Sauv&re, R. ; Normant, J.F. TefruhedronL&r. 1981, 22, 957-958. 7. Hbfle, G. ; Steglich, W. Synfhesis1972, 619-621. 8. *aF NMR: Ether: -95.2 (E,97%), -91.1 (2,396); Acetate: -95.3 (E,93%), -91.2 (2,746).
(Received in France 30 July 1993; accepted 17 September 1993)
Tetrahedron Letten, Vol. 34, No. 47. pp. 75657566,1993 Printed in Great Britain
Pcrgamon Press Ltd
Stereoselective Syntheses of 3,3-difluoro-1-propene Derivatives F&d&ique TelBerl* and Raymond Sauv&& I-IMU,
hbomtoirc
da Mbdiateuta Cbimiqw,
Domaine de Btwcwy,
7 llm J. el P. weis% 78114 Mqny-laa-H~lu 2-L~bomtoim do Chimie dea Orgdbmda,
(haca)
moci6 8u CNRS, Univcmitc P. c( hi. Curie,
botta 183.4 phce Jussieu,75252 Puis Cdcx 05 (&ace)
Abstntcf: A highIy regia- and stam~eluviw intmdnaion 40 lhe kq step is the treatment qf 3-acet~I.ld&luorA-ptvpe~ and lithium salts.
d@~~mmethylene gtvup in a&k pasition is dacribad with Grigtumi reagents in the presence of wpper
During the past few years, fluorinated organic molecules have drawn much attention due to their unique biological properties. The replacement of hydrogen atoms by fluorine atoms in biological molecules causes only a small steric perturbation but leads to major changes in hydrophobicity and polarity of the hydrocarbon chaint. Some syntheses allowing to prepare products in which a methylene group a to the double bond is replaced by a CF2 group have been describ&5. Herein, we report an efficient method for the incorporation of a difluoromethylene group in an allylic position. We show its application to the synthesis of various alkenes and styrenes. R’R’CzO
Table.
1) CFp=CHLI ____t 2) CH,COCl
R’R’C(OAc)-CHzCF,
Rt
R2
R3
X
Yielda
wzb
n-Hex n-Hex n-Hex n-Hex lhienyl
H H H H H
Me n-Bu i-Er t-Bu t-Bu i-Er
Br Br Br Cl Cl Br
(%) 75c 95 94d 95 70 85
9713 9812 97i3 9515 10010 __
(Cw 5
R’MgX CUCN ) LICI
R’R’CsCH-CF?-R’
19FNMR-&ppm)ICFCl,
Experimental conditions 24hl2O”C 8h/-15°C 2h/-20°C 3h/-20°C lh/-20°C 1h/-30°C
a: yield for the second step; b: E/Z ratio determined by teF NMR; c: containing also 15% of HexCH(Me)CH=C!FMe (Z/E=4/1); d: 80% with only 2 eq. of RsMgX. Our procedure is based on two key steps; an initial reaction between difluorovinyl lithium, prepared with 1, ldifluoroethylene and s-BuLi, and various carbonyl compounds leads to the allylic B,B-difluorinated 7565
7566
alcoxidese, which are acetylated in situ. Secondly, the intermediate acetates are attacked by Grignard reagents in the presence of copper and lithium salts via an S$‘, substitution reaction of an acetate moiety by an alkyl group, to afford the corresponding allylic difluorinated compounds with high regio- and stereoselectivities (no product of SN2 is present and if Rz=H, the E isomer is major (2 95 96)). Experimental procedure: the treatment of carbonyl derivatives with 2,2_difluorovinyl lithium, prepared in sifu from l,l-difluoroethylene
and s-BuLi in THF and Es0
@O/20) at -100°C (15 min), leads to the
difluorinated alcoxides which are acetylated in siru with AcCl (addition at -50°C then 30 min at O’C). In the case where Rt,R2=(CH2)5,
the alcohol is isolated and acetylated (Ac20, 4-DMAP, CH&$,
+2O”C,
2h)‘. To these intermediate acetates (5. 1O-3mol,l eq.), in the presence of CuCN (3 eq.) and LiCl (3 eq.) in THF (40 ml), is added the Grignard reagent (3eq.) (see Table) to afford the allylic difluorinated products which are then purified by flash silica-gel chromatography (pentane). This methodology is exemplified by the preparation of the difluoromethylene allylic analogue of Q-5decenyl acetate, a sex pheromonal component of Grupholifumolesra(oriental fruit moth). Previously, Fried ef al. have reported a synthesis of the same difluorinated analog&t. tEUO(CH~)~MgCI
Ac20 =
pr*
CuCN,LICl
CF,(CH@tBu
-
Pr\//\ FeCl,
CF2(CH&OAc
OAc
The protected Grignard reagent reacts with the adequate acetate to afford the corresponding difluoride ether in 65% yield (steric purity=97%)s.
allylic
The ether function is then deprotected into the acetate
with A%0 and FeCl, in E%O (80% yield, steric purity=93%)s. In conclusion,
this route appears to be a general and highly regioselective method for the allylic
introduction of a difluoromethylene
group into various alkenes and styrenes. This reaction allows us to
prepare readily products of high stereoisomeric and chemical purities, in good overall yields and in two steps from available starting materials. Acknowledgements: lhe authors thank PI@. J.F. Normaru and C. L&coins for helpfur discussions. lhis work was supported by lNRA and Ch!RS. We are indebted to Elf-&o&em for a generous gl@ of ISdifluoroethylene. References and notes 1. Prestwich, G.D. Pestic. Sci. 1986, 37, 430-440.
Prestwich, G.D. ‘; Sun, W.C. ; Mayer, MS. ; Dickens, J.C. J. Chem. Ecol. 1990, Id, 1761-1789. 2. Hasek, W.R. ; Smith, W.C. ; Engelhart, V.A. J. Am. Chem. Sot. l!MO,82,543-551. 3. Kwok, P.Y. ; Muellner, F.W. ; Chen, C.K. ; Fried, J. J. Am. Chem. Sot. 1987,109, 3684-3692; 4. Masnyk, M. ; Fried, J. ; Roelofs, W. TetrahedronLerr. 1989, 30, 3243-3246; 5. Sun, W.C. ; Ng, C.S. ; Prestwich, G.D. J. Org. Chem. 1992,57, 132-137. 6. Sauv&re, R. ; Normant, J.F. TefruhedronL&r. 1981, 22, 957-958. 7. Hbfle, G. ; Steglich, W. Synfhesis1972, 619-621. 8. *aF NMR: Ether: -95.2 (E,97%), -91.1 (2,396); Acetate: -95.3 (E,93%), -91.2 (2,746).
(Received in France 30 July 1993; accepted 17 September 1993)